Fenofibrate, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid-1-methylethyl ester, is a lipid regulating agent. It can reduce the total cholesterol and triglyceride levels in human. Fenofibrate is usually orally administered. After oral administration, fenofibrate is metabolized in vivo to fenofibric acid. In fact, fenofibric acid is the active molecule for fenofibrate's biological functions. Thus, fenofibric acid, which demonstrates better solubility compared to fenofibrate, is a preferred chemical entity for the treatment or prevention of endogenous hyperlipidaemias, hypercholestero laemias, and hypertriglyceridaemias.
Various crystalline salts of the fenofibric acid have been investigated to optimize fenofibric acid's pharmaceutical properties. The preparation and use of some crystalline salts of fenofibric acid, including choline salt, tromethamine salt, calcium salt, diethanolamine salt, lysine salt, piperazine salt, ethanolamine salt, meglumine salt, and sodium salt have been disclosed. Among all the existing fenofibric acid salts is the choline salt of fenofibric acid.
The fenofibric acid salt with choline is the drug substance in the commercial drug product, Trilipix® (fenofibric acid capsules). However, an inherent disadvantage of using a choline salt in any pharmaceutical manufacture process or composition is the potential hazard of a choline compound, e.g. choline hydroxide or choline chloride. A choline compound can cause skin irritation, serious eye irritation, or respiratory irritation.
Another disadvantage of using a choline salt in any pharmaceutical manufacture process or composition is the instability of the choline counter ion. Through degradation, a choline molecule produces some undesired by-products, which lead to some negative consequences, such as a strong smell and color darkening for any product containing choline molecule. The instability of a choline molecule also causes any commercial pharmaceutical product to have a shorter shelf life or to require more constrained conditions for the product's handling, transportation, and storage.
Thus, it is still desirable to identify other fenofibric acid salts with better physicochemical properties, which in turn improves the manufacture process and medical use of fenofibric acid as an active therapeutic agent.
Unlike other conventional counter ions, berberine, as well as its analogues, is seldom included in a salt screening for any pharmaceutical composition. This may be due to the fact that berberine is usually commercially available as a salt, e.g. hydrochloride salt or hydrogen sulfate salt, which cannot be directly used in a traditional salt screening. In fact, the current disclosure represents the first example to use berberine or its analogues as basic counter ions to produce a new crystalline pharmaceutical salt for any pharmaceutical active agent.
Accordingly, it is an objective of the disclosure to provide solid and/or crystalline fenofibric acid salts with berberine or its analogues.
It is also an objective of this disclosure to provide pharmaceutical compositions comprising the crystalline fenofibric acid salts with berberine or its analogues disclosed herein.
It is an additional objective of this disclosure to provide a method to generate a salt using berberine or its analogs as counter ions in salts of any active pharmaceutical agent.
It is another objective of this disclosure to provide a new chemical entity having from 1:2 to 2:1, preferably 1:1 fixed ratio of fenofibric acid and berberine as co-drug for treatment of cardiovascular diseases or other diseases.
The solid and/or crystalline fenofibric acid salts with berberine or its analogues disclosed herein use natural pyridinium cations with anions of an active pharmaceutical agent in a salt and can be used alone in a pharmaceutical or dietary composition alone or with other pharmaceutical active or beneficial agent(s) for treatment or prevention of cardiovascular diseases or conditions. The crystalline fenofibric acid salts disclosed herein provide improved salt forms that uses a different counter ion, e.g., berberine or its analog, and eliminate harmful effects that are associated with the existing fenofibric acid salts, such as choline as in the commercially available Trilipix®. Thus, the crystalline salts disclosed herein provide improved chemical entities to be used in a pharmaceutical composition alone or in combination with other drug substances.
Other objects, advantages and features of the present disclosure will become apparent from the following specification taken in conjunction with the accompanying examples or drawings.